Is the PROTECT (Program to Research Omnibus Treatment Efficacy and Safety in Patients with Clear Cell Renal Cell Carcinoma) trial relevant to the adjuvant setting for a patient with a history of clear cell renal cell carcinoma (RCC) who has undergone a recent nephrectomy?

Is the PROTECT Trial in the Adjuvant Setting?

Yes, the PROTECT trial is an adjuvant therapy trial that evaluated pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma at high risk of relapse. 1

Trial Design and Population

The PROTECT trial was a randomized, double-blind, placebo-controlled phase 3 study that enrolled 1,538 patients with resected clear cell RCC. 2

Eligibility criteria included:

• Patients with resected pT2 (high grade) or ≥ pT3 disease, including N1 2
• Locally advanced RCC at high risk of relapse after nephrectomy 3
• Clear cell histology 2

Treatment regimen:

• Pazopanib versus placebo for 1 year 2
• Initial starting dose of 800 mg was reduced to 600 mg due to toxicity attrition 2
• The primary endpoint was changed to disease-free survival (DFS) for pazopanib 600 mg versus placebo (n = 1,135) 2

Trial Results

The PROTECT trial was negative for its primary endpoint. 1

Primary analysis findings:

• DFS with pazopanib 600 mg showed no significant improvement over placebo (HR 0.86; 95% CI 0.70-1.06; P = 0.165) 2
• Follow-up analysis in the 600 mg group yielded an HR of 0.94 (95% CI 0.77-1.14) 2
• Secondary analysis of DFS in the 800 mg group (n = 403) yielded an HR of 0.69 (95% CI 0.51-0.94), but this was not the primary endpoint 2

Overall survival analysis:

• Final OS analysis showed no significant difference between pazopanib and placebo arms (HR 1.0; 95% CI 0.80-1.26; nominal p > 0.9) 3
• Median follow-up was 76 months for pazopanib and 77 months for placebo 3

Clinical Implications

Pazopanib is not recommended as adjuvant therapy following resection of locally advanced RCC. 3

The PROTECT trial, along with ASSURE and S-TRAC, was included in a pooled analysis that did not reveal a statistically significant effect of adjuvant VEGFR-targeted therapy on improved DFS or OS in patients with intermediate-/high-risk local or regional fully resected RCC. 1

Current guideline recommendations:

• The European Association of Urology advises against using pazopanib in the adjuvant setting, except in exceptional circumstances with informed consent about lack of OS benefit 4
• Observation remains the standard of care when pembrolizumab is unavailable or contraindicated 4

Common toxicities leading to discontinuation:

• Increased ALT (16% in 600 mg group, 18% in 800 mg group) 2
• Increased AST (5% in 600 mg group, 7% in 800 mg group) 2